Cell cycle inhibition of HTLV-I transformed T cell lines by retinoic acid: the possible therapeutic use of thioredoxin reductase inhibitors.

Adult T cell leukemia derived factor (ADF), which was first reported as a cytokine-like factor produced by human T lymphotropic virus I (HTLV-I)-transformed T cells, is a human homologue of thioredoxin (TRX). ADF/TRX has multiple functions including growth promoting, antiapoptotic and radical scavenging activities, and is also involved in a wide variety of intracellular processes as a dithiol reducing agent in cooperation with the NADPH-TRX reductase system. In HTLV-1(+) T cell lines, HuT 102 and MT-2, which are ADF/TRX high producing cells, we found that the expression of ADF/TRX was dependent on the cell cycle and peaked at S phase. The reducing activity of ADF/TRX in these cells was also dependent on the cell cycle and elevated in S phase as determined by NADPH-dependent insulin degradation assay. Furthermore, inhibitors of TRX reductase, 13-cis-retinoic acid (13-cis-RA) and azelaic acid, inhibited the DNA synthesis of these cells. In contrast, the residual expression and reducing activity of ADF/TRX in HTLV-I(-) T cell lines did not show any significant correlation with the cell cycle. There was no distinct inhibitory effect of 13-cis-RA or azelaic acid on the growth of these ADF/TRX low producing cells. These results indicate that a high level of reducing activity of the ADF/TRX system may be required for the cell division of these virally transformed cells. This suggests that the TRX reductase inhibitors including retinoid derivatives have a potential therapeutic utility for treatment of HTLV-1(+) T cell leukemia without any effect on HTLV-I(-) cells.